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Purpose: Several international organizations advocate for monitoring of adherence to direct oral anticoagulants (DOACs), given the prevalent issue of suboptimal adherence to DOACs. The aim was to investigate intake patterns in patients on DOAC therapy by electronic monitoring of medication adherence in community pharmacies (using a Medication Event Monitoring System ® (MEMS ® )-device), and to assess patients' experiences with this device., Patients and Methods: Patients using apixaban, rivaroxaban or edoxaban and visiting a community pharmacy, were included. Adherence was electronically monitored over a twelve-week period. Pharmacists conducted data readings from the electronic device at six and twelve weeks, and discussed these data with the patients. At the beginning and end of the study, patients completed a questionnaire about their expectations and experiences respectively., Results: Eighty-nine patients were included and high taking adherence rates were observed (median adherence of 100% for once-daily dosed patients and 96.7% for twice-daily dosed patients), but more than half of the patients took at least one dose too late or skipped at least one dose, possibly resulting in temporarily reduced protection against thromboembolic events. Most patients who felt that their adherence had improved, believed this was due to the combination of the electronic device and the personal follow-up by the pharmacist. Although most patients stated that medication adherence is their own responsibility, they were grateful for the support they received from their community pharmacist., Conclusion: High adherence rates were observed, but there was still room for improvement regarding intake moments. Positive experiences with an electronic device for medication adherence monitoring were reported., Competing Interests: Antoine Pironet reports employment relationship with AARDEX Group. The other authors have no relevant financial or non-financial interests to disclose for this work., (© 2024 Desmaele et al.)

Aims: Bleeding events are a well-known complication of oral anticoagulant (OAC) use in patients with atrial fibrillation (AF). While these are undesirable, bleedings could have a warning potential for underlying tumoural lesions. Therefore, we aimed to investigate the association between anticoagulant-related bleeding and newly diagnosed tumoural lesions in a nationwide cohort study., Methods and Results: Using Belgian nationwide data, AF patients without any tumoural lesions were included when initiating OACs between 2013 and 2019. The absolute and relative risks of newly diagnosed tumoural lesions were investigated in OAC users with vs. without an OAC-related bleeding event. Analyses were additionally stratified by tumoural lesion, location-specific bleeding, and OAC type. A total of 230 386 OAC users were included, among whom 35 192 persons were diagnosed with a tumoural lesion during follow-up. Persons with a clinically relevant bleeding during OAC use had a tumoural lesion incidence of 15.33 per 100 person-years compared to an incidence of 5.22 per 100 person-years in persons without bleeding. Site-specific gastrointestinal, urogenital, respiratory, and intracranial bleeding events were respectively associated with a significantly increased risk of incident gastrointestinal [adjusted hazard ratio (aHR) 8.13 (95% confidence interval (CI): 7.08-9.34)], urological [aHR 12.73 (95% CI: 10.56-15.35)], respiratory [aHR 4.91 (95% CI: 3.24-7.44)], and intracranial tumoural lesions [aHR 27.89 (95% CI: 16.53-47.04)]., Conclusion: Bleeding events in AF patients initiated on OAC were associated with an increased risk of tumoural lesions. Therefore, OAC-related bleeding events could unmask an underlying tumoural lesion., Competing Interests: Conflict of interest: None declared related to this manuscript. Outside this manuscript, L.L. received consulting fees paid to her institution from AstraZeneca, GSK and Sanofi and has given a lecture sponsored by Chiesi. L.L. and M.G. have given lectures sponsored by IPSA vzw, and L.L. to Domus Medica vzw (both non-profitorganisations facilitating lifelong learning for healthcare providers). S.R. received consulting fees from MSD, BMS, Pfizer and Ipsen., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Assessing medication adherence is crucial in chronic obstructive pulmonary disease (COPD) management to prevent exacerbations. However, it is unclear whether this association between adherence and exacerbations is influenced by the adherence assessment methods or thresholds used. Electronic healthcare databases are valuable to study exacerbations and adherence in real life. We aimed to systematically review the literature to identify adherence assessment methods and thresholds used in healthcare databases when investigating the association between medication adherence and COPD exacerbations and to meta-analyse the associated effect sizes., Method: MEDLINE, Web of Science and Embase were searched for peer-reviewed articles, written in English, published up to 10 October 2022 (PROSPERO: CRD42022363449). Two reviewers independently conducted screening for inclusion and performed data extraction. A qualitative approach described the adherence assessment methods and thresholds used. A quantitative approach (meta-analysis using random effects model) estimated the association between adherence and the risk of COPD exacerbations., Results: Eight studies were included in the systematic review of which five studies were included in the meta-analysis. The medication possession ratio (MPR) and the proportion of days covered (PDC) were the adherence assessment methods used and 0.80 was always used as threshold to differentiate good from poor adherence. Adherence and exacerbations were mostly measured over the same time period. Poor adherence (MPR or PDC<0.80) was significantly associated with a higher COPD exacerbation risk (OR 1.40, 95% CI 1.21 to 1.62, I 2 =85%), regardless of the adherence assessment method used. Results were consistent when stratified by exacerbation severity. Poor adherence was also associated with a time-dependent risk of COPD exacerbations (incidence rate ratio 1.31, 95% CI 1.17 to 1.46)., Conclusion: Our systematic review with meta-analysis demonstrated a 40% increased risk of COPD exacerbations in case of poor adherence to inhaler medication., Prospero Registration Number: CRD42022363449., Competing Interests: Competing interests: Outside this manuscript, LL received a consulting fee paid to her institution from AstraZeneca, GSK and Sanofi and has given a lecture sponsored by Chiesi. Outside this manuscript, LL and MG have given lectures sponsored by IPSA vzw, a non-profit organisation facilitating lifelong learning for healthcare providers. Neither author has received any fees personally. LL is an unpaid member of European Respiratory Society and Belgian Respiratory Society, member of Faculty Board of Ghent University–Faculty of Pharmaceutical Sciences and faculty committees., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Current research on potentially inappropriate prescribing (PIP) in polymedicated older adults with atrial fibrillation (AF) and multimorbidity is predominantly focused on PIP of oral anticoagulants (OAC). Our study aimed to assess (i) the overall prevalence of PIP in older multimorbid adults with AF, (ii) potential associated factors of PIP, and (iii) the association of PIP with adverse health outcomes in a nationwide sample of Swedish older adults., Methods: Swedish national registries were linked to establish a cohort with a 2-year follow-up of older adults (≥65y) who, on 1 January 2017, had a diagnosis of AF and had at least one comorbidity (n = 203,042). PIP was assessed using the reduced STOPP/START version 2 screening tool. The STOPP criteria identify potentially inappropriate prescribed medications (PIM), while the START criteria identify potential prescribing omissions (PPO). PIP is identified as having at least one PIM and/or PPO. Cox regression analyses were conducted to examine the association between PIP and adverse health outcomes: mortality, hospitalisation, stroke, bleeding, and falls., Results: PIP was highly prevalent in older adults with AF, with both polypharmacy (69.6%) and excessive polypharmacy (85.9%). In the study population, benzodiazepines (22.9%), hypnotic Z-medications (17.8%) and analgesics (8.7%) were the most frequent PIM. Anticoagulants (34.3%), statins (11.1%), vitamin D and calcium (13.4%) were the most frequent PPO. Demographic factors and polypharmacy were associated with different PIM and PPO categories, with the nature of these associations differing based on the specific type of PIM and PPO. The co-occurrence of PIM and PPO, compared to appropriate prescribing, was associated with an increased risk of adverse health outcomes compared to all appropriately prescribed medications: cardiovascular (CV) (Hazard ratio (HR) [95% confidence interval] = 1.97 [1.88-2.07]) and overall mortality (HR = 2.09 [2.03-2.16]), CV (HR = 1.34 [1.30-1.37]) and overall hospitalisation (HR = 1.48 [1.46-1.51]), stroke (HR = 1.93 [1.78-2.10]), bleeding (HR = 1.10 [1.01-1.21]), and falls (HR = 1.63 [1.56-1.71])., Conclusion: The present study reports a high prevalence of PIP in multimorbid polymedicated older adults with AF. Additionally, a nuanced relationship between prescribing patterns, patient characteristics, and adverse health outcomes was observed. These findings emphasise the importance of implementing tailored interventions to optimise medication management in this patient population., Competing Interests: MG declares that he received a research grant from the Research Foundation Flanders (project number 11C0820N). Additionally, he declares payment to his institution for giving lectures to IPSA, a non-profit organisation. GL declares consultancy and speaker fees from BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. MP declares that he is the President of the European Geriatric Medicine Society. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Amrouch, Vetrano, Damiano, Dai, Calderón-Larrañaga, Grymonprez, Proietti, Lip, Johnsen, Wastesson, Johnell, De Smedt and Petrovic.)

Introduction: Direct oral anticoagulants (DOACs) are increasingly used and can be involved in clinically relevant drug-drug interactions (DDIs) that increase the risk of major bleeding or thromboembolism. Skilled drug interaction management is essential to ensure safe and effective use of DOACs. In this study, we aimed to investigate the impact of the detection and management of DDIs with DOACs in a real-life community pharmacy setting on the pharmacotherapy of DOAC users., Methods: We conducted an intervention study in 201 community pharmacies in Belgium. On random days, patients purchasing DOACs or drugs known to interact with them were screened. When a DDI with the DOAC was detected, the pharmacist contacted the prescribing physician to discuss the management of the interaction. A previously developed practice-oriented DDI list accompanied by management plans for ambulatory care was used for both screening and management of the DDIs., Results: In total, 751 patients were included, among whom 875 DDIs were identified, primarily pharmacodynamic DDIs (95.7 %). Predominant interacting drug classes included selective serotonin or serotonin and norepinephrine reuptake inhibitors (32.9 %), antiplatelets (30.9 %), and non-steroidal anti-inflammatory drugs (28.9 %). In 43.0 % of DDIs, an intervention was decided upon. At three-month follow-up, proposed pharmacotherapy changes had been implemented in 79.1 % of these DDIs., Conclusions: This study demonstrates that active screening and management of DDIs with DOACs in community pharmacies, in close collaboration with prescribing physicians, resulted in changes in pharmacotherapy in a substantial number of patients. This may contribute significantly to the safer utilisation of DOACs in high-risk populations., Competing Interests: Declaration of competing interest Outside this manuscript, MG and LL have given lectures sponsored by IPSA vzw, a non-profit organisation facilitating lifelong learning for community pharmacists. No author has received any fees personally. All other authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background:  Polypharmacy may affect outcomes in patients with atrial fibrillation (AF) using non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) due to interactions or reduced adherence, but comparative data are lacking. Therefore, the impact of polypharmacy on AF-related outcomes and benefit-risk profiles of NOACs in patients with polypharmacy were investigated., Methods:  AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate outcomes., Results:  Among 254,478 AF patients, 167,847 (66.0%) used ≥5 drugs. Polypharmacy was associated with higher stroke or systemic embolism (stroke/SE) (adjusted hazard ratio [aHR]: 1.08, 95% confidence interval [CI]: 1.02-1.15), all-cause mortality (aHR: 1.45, 95% CI: 1.40-1.50), and major bleeding risks (aHR: 1.29, 95% CI: 1.23-1.35). Among patients with polypharmacy, NOACs were associated with lower stroke/SE (aHR: 0.68, 95% CI: 0.63-0.73), all-cause mortality (aHR: 0.80, 95% CI: 0.77-0.84), major bleeding (aHR: 0.92, 95% CI: 0.87-0.97), and intracranial bleeding risks (aHR: 0.77, 95% CI: 0.69-0.85), but higher gastrointestinal bleeding risks (aHR: 1.10, 95% CI: 1.01-1.19) compared to VKAs. Major bleeding risks were lower with apixaban (aHR: 0.79, 95% CI: 0.74-0.85), but nonsignificantly different with other NOACs compared to VKAs. Lower major bleeding risks were observed with dabigatran (aHR: 0.91, 95% CI: 0.85-0.97) and apixaban (aHR: 0.77, 95% CI: 0.73-0.81) compared to rivaroxaban, and with apixaban compared to dabigatran (HR: 0.83, 95% CI: 0.77-0.90) and edoxaban (HR: 0.77, 95% CI: 0.70-0.85)., Conclusion:  Polypharmacy was associated with increased thromboembolic, bleeding, and mortality risks in AF patients. NOACs had better benefit-risk profiles than VKAs in patients with polypharmacy., Competing Interests: Outside this manuscript, T.D.B. has served as a chairperson during a lecture for Bayer and Daiichi Sankyo and participated in an expert meeting for Pfizer. Outside this manuscript, L.L. has been consulted as an expert for AstraZeneca. Outside this manuscript, M.P. and S.S. have given a lecture sponsored by BMS, L.L. a lecture sponsored by Chiesi, and S.S., L.L., and M.G. lectures sponsored by IPSA vzw, a nonprofit organization facilitating lifelong learning for health care providers. None of the authors has received any fees personally., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Aims: Data on non-vitamin K antagonist oral anticoagulants (NOACs) use in patients with atrial fibrillation (AF) and frailty are scarce. Therefore, the impact of frailty on AF-related outcomes and benefit-risk profiles of NOACs in patients with frailty were investigated., Methods and Results: AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Frailty was assessed with the Claims-based Frailty Indicator. Among 254 478 anticoagulated AF patients, 71 638 (28.2%) had frailty. Frailty was associated with higher all-cause mortality risks [adjusted hazard ratio (aHR) 1.48, 95% confidence interval (CI) (1.43-1.54)], but not with thromboembolism or bleeding. Among subjects with frailty (78 080 person-years of follow-up), NOACs were associated with lower risks of stroke or systemic embolism (stroke/SE) [aHR 0.77, 95%CI (0.70-0.86)], all-cause mortality [aHR 0.88, 95%CI (0.84-0.92)], and intracranial bleeding [aHR 0.78, 95%CI (0.66-0.91)], a similar major bleeding risk [aHR 1.01, 95%CI (0.93-1.09)], and higher gastrointestinal bleeding risk [aHR 1.19, 95%CI (1.06-1.33)] compared with VKAs. Major bleeding risks were lower with apixaban [aHR 0.84, 95%CI (0.76-0.93)], similar with edoxaban [aHR 0.91, 95%CI (0.73-1.14)], and higher with dabigatran [aHR 1.16, 95%CI (1.03-1.30)] and rivaroxaban [aHR 1.11, 95%CI (1.02-1.21)] compared with VKAs. Apixaban was associated with lower major bleeding risks compared with dabigatran [aHR 0.72, 95%CI (0.65-0.80)], rivaroxaban [aHR 0.78, 95%CI (0.72-0.84)] and edoxaban [aHR 0.74, 95%CI (0.65-0.84)], but mortality risk was higher compared with dabigatran and edoxaban., Conclusion: Frailty was an independent risk factor of death. Non-vitamin K antagonist oral anticoagulants had better benefit-risk profiles than VKAs in patients with frailty, especially apixaban, followed by edoxaban., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflicts of interest T.H. has received grants and consulting and/or speaking fees from AbbVie, Johnson & Johnson, Pfizer, BMS, Boehringer Ingelheim, Celgene, Lilly, MSD, Biogen, LEO Pharma, Amgen and UCB. S.V. has received grants from AbbVie, Johnson & Johnson, Pfizer, Galápagos and Takeda, and has received consulting and/or speaking fees from AbbVie, AbolerIS Pharma, Agomab, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galápagos, Genentech-Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrM Health, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma and Zealand Pharma.

Aims: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated., Methods and Results: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality., Conclusion: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Pharmacodynamic drug-drug interactions (PD DDIs) may influence the safety of non-vitamin K antagonist oral anticoagulants (NOACs), but the extent to which PD DDIs increase bleeding risks, remains unclear. Therefore, the impact of PD DDIs on bleeding outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated., Methods: Using Belgian nationwide data, NOAC-treated AF patients were included between 2013-2019. Concomitant use of PD interacting drugs when initiating NOAC treatment was identified., Results: Among 193,072 patients, PD DDIs were identified in 114,122 (59.1%) subjects. After multivariable adjustment, concomitant use of PD interacting drugs was associated with significantly higher risks of major or clinically-relevant non-major bleeding (adjusted hazard ratio (aHR) 1.19, 95% confidence interval (CI) (1.13-1.24)), gastrointestinal (aHR 1.12, 95%CI (1.03-1.22)), urogenital (aHR 1.21, 95%CI (1.09-1.35)) and other bleeding (aHR 1.28, 95%CI (1.20-1.36)), compared to NOAC-treated AF patients without PD interacting drug use. Increased bleeding risks were most pronounced with P2Y 12 inhibitors (aHR 1.62, 95%CI (1.48-1.77)) and corticosteroids (aHR 1.53, 95%CI (1.42-1.66)), followed by selective serotonin or serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI, aHR 1.26, 95%CI (1.17-1.35)), low-dose aspirin (aHR 1.14, 95%CI (1.08-1.20)) and non-steroidal anti-inflammatory drugs (NSAID, aHR 1.10, 95%CI (1.01-1.21)). Significantly higher intracranial bleeding risks in NOAC users were observed with SSRI/SNRIs (aHR 1.50, 95%CI (1.25-1.81)) and corticosteroids (aHR 1.49, 95%CI (1.21-1.84))., Conclusion: Concomitant use of PD interacting drugs, especially P2Y 12 inhibitors and corticosteroids, was associated with higher major, gastrointestinal, urogenital, and other bleeding risks in NOAC-treated AF patients. Remarkably, higher intracranial bleeding risks were observed with SSRI/SNRIs and corticosteroids., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effect of NOACs is currently unknown. Therefore, we investigated thresholds of NOAC adherence in association with thromboembolic and mortality risks., Methods: Patients with AF initiating NOACs between 2013 and 2019 were identified in Belgian nationwide data. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability of treatment weighted Cox regression was used to investigate outcomes., Results: 92,111 persons were included (250,750 person-years). Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85-89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19-1.54)), 80-84% (aHR 1.31, 95%CI (1.08-1.58)) and < 80% (aHR 1.64, 95%CI (1.34-2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95-99% (aHR 1.02, 95%CI (0.94-1.12)) or 90-94% (aHR 1.06, 95%CI (0.95-1.18)). Significantly higher risks of all-cause mortality were observed with decreasing levels of NOAC adherence, which were already higher among NOAC users with a one-year PDC of 90-94% versus 100% (aHR 1.09, 95%CI (1.01-1.17)). Findings were similar with once-daily and twice-daily dosed NOACs., Conclusion: Poor adherence to NOACs is associated with increased risks of thromboembolism and all-cause mortality. The minimal adherence threshold should be ≥ 90%, preferably even ≥ 95%., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs., Methods: Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method., Results: Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24-3.72)) than VKAs., Conclusion: The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Data on non-vitamin K antagonist oral anticoagulant (NOAC) use in patients with atrial fibrillation (AF) and a history of falls are limited. Therefore, we investigated the impact of a history of falls on AF-related outcomes, and the benefit-risk profiles of NOACs in patients with a history of falls., Methods: Using Belgian nationwide data, AF patients initiating anticoagulation between 2013 and 2019 were included. Previous falls that occurred ≤ 1 year before anticoagulant initiation were identified., Results: Among 254,478 AF patients, 18,947 (7.4%) subjects had a history of falls, which was associated with higher risks of all-cause mortality (adjusted hazard ratio (aHR) 1.11, 95%CI (1.06-1.15)), major bleeding (aHR 1.07, 95%CI (1.01-1.14)), intracranial bleeding (aHR 1.30, 95%CI (1.16-1.47)) and new falls (aHR 1.63, 95%CI (1.55-1.71)), but not with thromboembolism. Among subjects with a history of falls, NOACs were associated with lower risks of stroke or systemic embolism (aHR 0.70, 95%CI (0.57-0.87)), ischemic stroke (aHR 0.59, 95%CI (0.45-0.77)) and all-cause mortality (aHR 0.83, 95%CI (0.75-0.92)) compared to vitamin K antagonists (VKAs), while major, intracranial, and gastrointestinal bleeding risks were not significantly different. Major bleeding risks were significantly lower with apixaban (aHR 0.77, 95%CI (0.63-0.94)), but similar with other NOACs compared to VKAs. Apixaban was associated with lower major bleeding risks compared to dabigatran (aHR 0.78, 95%CI (0.62-0.98)), rivaroxaban (aHR 0.78, 95%CI (0.68-0.91)) and edoxaban (aHR 0.74, 95%CI (0.59-0.92)), but mortality risks were higher compared to dabigatran and edoxaban., Conclusions: A history of falls was an independent predictor of bleeding and death. NOACs had better benefit-risk profiles than VKAs in patients with a history of falls, especially apixaban., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Outside this manuscript, TDB has served as a chairperson during a lecture for Bayer and Daiichi Sankyo and participated in an expert meeting for Pfizer. Outside this manuscript, LL has been consulted as expert for AstraZeneca. Outside this manuscript, MP and SS have given a lecture sponsored by BMS, LL a lecture sponsored by Chiesi, and SS, LL and MG lectures sponsored by IPSA vzw, a non-profit organization facilitating lifelong learning for pharmacists. No author has received any fees personally.’, (© 2023 The Authors.)

Aim: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly preferred over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management. However, differences in oral anticoagulant (OAC) prescribing according to patient's age, sex and physician's specialty may be present. Therefore, incident and prevalent use of OACs, NOACs and VKAs, stratified by age, sex and prescriber, and factors associated with the choice of OAC were investigated., Methods: Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 OAC prescription claim between 2013 and 2019 were identified. OAC use was investigated per half-year. Factors influencing NOAC vs. VKA initiation were identified by multivariable logistic regression., Results: Among 448 661 included OAC-treated AF patients, 297 818 were newly treated. Incident OAC use ranged from 45-49 to 42-44 users/10 000 persons between 2013 and 2019, whereas prevalent OAC use increased from 337 to 435 users/10 000 persons. Incident and prevalent NOAC use exceeded VKA use since 2013 and 2015, respectively, and NOACs represented 92% of incident and 81% of prevalent OAC users in 2019. Apixaban was the most frequently used NOAC since 2016. NOACs were significantly more prescribed by cardiologists and to older patients, whereas VKAs were more initiated in patients with cardiovascular, renal and hepatic comorbidities. Prevalent OAC use increased less in women than men (25.3% vs. 33.0% between 2013 and 2019) and female subjects had 5% significantly lower odds of NOAC vs. VKA initiation than men., Conclusion: Since 2013, prevalent anticoagulant use increased almost one third in Belgium, while incident use was stable. Potential (N)OAC underuse in women requires further exploration., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs., Methods: AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes., Results: Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95% CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95% CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95% CI (0.88-1.11)). Apixaban (aHR 0.91, 95% CI (0.83-0.99)) and edoxaban (aHR 0.79, 95% CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban., Conclusion: NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct long-term head-to-head comparisons are lacking. Therefore, their risk-benefit profiles were investigated compared to VKAs and between NOACs. Methods: AF patients initiating anticoagulation between 2013-2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes and were additionally stratified by NOAC dose. Results: Among 254,478 AF patients (328,796 person-years of follow-up), NOACs were associated with significantly lower risks of stroke or systemic embolism (stroke/SE) (hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.64-0.72)), all-cause mortality (HR 0.76, 95%CI (0.74-0.79)), major or clinically relevant non-major bleeding (MB/CRNMB) (HR 0.94, 95%CI (0.91-0.98)) and intracranial hemorrhage (HR 0.73, 95%CI (0.66-0.79)), but non-significantly different risks of myocardial infarction, gastrointestinal and urogenital bleeding compared to VKAs. Despite similar stroke/SE risks, dabigatran and apixaban were associated with significantly lower MB/CRNMB risks compared to rivaroxaban (HR 0.86, 95%CI (0.83-0.90); HR 0.86, 95%CI (0.83-0.89), respectively) and edoxaban (HR 0.91, 95%CI (0.83-0.99); HR 0.86, 95%CI (0.81-0.91), respectively), and apixaban with significantly lower major bleeding risks compared to dabigatran (HR 0.86, 95%CI (0.80-0.92)) and edoxaban (HR 0.79, 95%CI (0.72-0.86)). However, higher mortality risks were observed in some risk groups including with apixaban in patients with diabetes or concomitantly using digoxin compared to dabigatran and edoxaban, respectively. Conclusion: NOACs had better long-term risk-benefit profiles than VKAs. While effectiveness was comparable, apixaban was overall associated with a more favorable safety profile followed by dabigatran., Competing Interests: Outside this manuscript, TDB has served as a chairperson during a lecture for Bayer and Daiichi Sankyo, and participated in an expert meeting for Pfizer. Outside this manuscript, SS has given a lecture sponsored by BMS. Neither author has received any fees personally. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Grymonprez, De Backer, Bertels, Steurbaut and Lahousse.)

Background: Since non-vitamin K antagonist oral anticoagulants (NOACs) do not require coagulation monitoring, concerns of lower adherence and persistence to NOACs than vitamin K antagonists (VKAs) have been raised. Moreover, little is known on the frequency of permanent cessation and switching between anticoagulants in patients with atrial fibrillation (AF). Therefore, persistence, reinitiation, switching and adherence to oral anticoagulants (OACs) were investigated., Materials and Methods: AF patients with a first OAC prescription claim between 2013 and 2019 were identified in Belgian nationwide data. Persistence, reinitiation and switching were estimated using Kaplan-Meier analyses. Adherence was investigated using the proportion of days covered (PDC). Predictors for non-adherence and non-persistence were identified by multivariable logistic regression., Results: Among 277,782 AF patients, 69.6% NOAC and 37.2% VKA users were persistent after 1 year, whereas 44.3% and 18.9% after 5 years, respectively. After one year, 67.1% rivaroxaban, 68.1% dabigatran, 69.8% apixaban, and 76.9% edoxaban users were persistent. Among subjects having discontinued NOAC or VKA treatment, 75.4% and 46.1% reinitiated any OAC within 5 years, respectively. VKAs were more frequently switched to NOACs than vice versa (17.6% versus 2.5% after 1 year). After 1 year, a high PDC (≥ 90%) was observed in 87.8% apixaban, 88.6% dabigatran, 91.3% rivaroxaban, and 94.7% edoxaban users (90.2% NOAC users). Adherence and persistence were higher in older, female subjects, while lower in subjects with dementia or hyperpolypharmacy., Conclusion: Adherence and persistence to NOACs were high. However, 10% of subjects were non-adherent after 1 year and one-fourth did not reinitiate anticoagulation within 5 years after NOAC discontinuation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grymonprez, Capiau, Steurbaut, Mehuys, Boussery, De Backer and Lahousse.)

Purpose: Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in the general AF population. However, as NOACs are administered in fixed doses, concerns of unintentional underdosing in morbidly obese patients and unintentional overdosing in underweight patients have emerged. Therefore, a critical appraisal of the benefit-risk profile of NOACs in AF patients across the body weight spectrum is needed., Methods and Results: After searching Medline, this systematic review discusses the impact of body weight on the risk-benefit profile of NOACs versus VKAs. The meta-analysis demonstrated that NOAC use in obese and class III obese AF patients (body mass index (BMI) ≥ 30 and ≥ 40 kg/m 2 , respectively) was associated with significantly lower stroke/systemic embolism (stroke/SE) risks (RR 0.82, 95%CI [0.71-0.96] and RR 0.75, 95%CI [0.64-0.87], respectively), similar to lower major bleeding risks (RR 0.83, 95%CI [0.69-1.00] and RR 0.74, 95%CI [0.57-0.95], respectively) and similar mortality risks (RR 0.92, 95%CI [0.73-1.15] and RR 1.17, 95%CI [0.83-1.64], respectively) compared to VKAs. In AF patients ≤ 60 kg, significantly lower stroke/SE (RR 0.63, 95%CI [0.56-0.71]) and major bleeding risks (RR 0.71, 95%CI [0.62-0.80]), but similar mortality risks (RR 0.68, 95%CI [0.42-1.10]), were observed for NOAC- versus VKA-treated patients., Conclusion: The benefit-risk profile of NOACs seems preserved in (morbidly) obese AF patients and patients with low body weight. However, more data are needed on underweight AF patients (BMI < 18.5 kg/m 2 ) and on differences between NOACs in these patients., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Non-vitamin K antagonist oral anticoagulants (NOACs) are effective and safe alternatives compared with vitamin K antagonists (VKAs) for thromboembolic prevention in atrial fibrillation (AF), while antiplatelets are no longer recommended. However, to which extent NOAC introduction and guideline updates have increased OAC use in AF, is unclear. Therefore, worldwide trends in real-life prescribing of OACs, NOACs, VKAs, and antiplatelet monotherapy in AF patients were investigated., Methods and Results: Using PubMed and Embase, observational nationwide cohort studies on annual prevalent and/or incident OAC use in non-selected AF patients since 2010 were included. A meta-analysis of single proportions was performed. Twenty-one studies were included assessing prevalent and incident use among 9 758 637 and 197 483 OAC-eligible AF patients, respectively. Worldwide prevalence and incidence of OAC users increased from 0.42 [95% confidence interval (CI) 0.22-0.65] and 0.43 (95% CI 0.37-0.49) in 2010 to 0.78 (95% CI 0.77-0.78) and 0.75 (95% CI 0.74-0.76) in 2018, respectively. Prevalent and incident NOAC users increased globally from 0 in 2010 to 0.45 (95% CI 0.45-0.46) and 0.68 (95% CI 0.67-0.69) in 2018, respectively, whereas prevalent and incident VKA use decreased from 0.42 (95% CI 0.22-0.65) and 0.42 (95% CI 0.36-0.49) in 2010 to 0.32 (95% CI 0.32-0.32) and 0.06 (95% CI 0.06-0.07) in 2018, respectively. Prevalent antiplatelet monotherapy use decreased from 0.37 (95% CI 0.32-0.42) in 2010 to 0.09 (95% CI 0.09-0.10) in 2018., Conclusion: The proportion of OAC users worldwide almost doubled following NOAC introduction. As one-quarter of OAC-eligible AF subjects were not anticoagulated and 9% were only treated with antiplatelets in 2018, there is still room for improvement., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated., Methods: A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients., Results: Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33])., Conclusion: Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted., (© 2022 British Pharmacological Society.)

Objectives: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cerebrovascular disease, which might be associated with decreases in cerebral blood flow. Since studies examining cerebral blood flow in COPD remain scarce and are limited by sample size, we aimed to study cerebral blood flow in participants with and without COPD., Design: Observational cohort study., Setting: Population-based Rotterdam Study., Participants: 4177 participants (age 68.0±8.5 years; 53% females) with and without COPD., Predictor Variable: Spirometry and pulmonary diffusing capacity., Outcome Measures: Cerebral blood flow by two-dimensional phase-contrast cerebral MRI., Results: Compared with subjects with normal spirometry (forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) ≥0.7 and FEV 1 ≥80%), multivariable adjusted cerebral blood flow (mL/min) was preserved in subjects with COPD Global initiative for Chronic Obstructive Lung Disease (GOLD1) (FEV 1 /FVC <0.7 and FEV 1 ≥80%), but significantly lower in subjects with COPD GOLD2-3 (FEV 1 /FVC <0.7 and FEV 1 <80%), even after adjustment for cardiovascular comorbidities. In sex-stratified analyses, this difference in cerebral blood flow was statistically significant in women but not in men. Cerebral blood flow was lowest in subjects with FEV 1 , FVC and diffusion lung capacity for carbon monoxide % predicted values in the lowest quintile, even after adjustment for cardiovascular comorbidities and cardiac function., Conclusion: We observed a lowered cerebral blood flow in subjects with COPD GOLD2-3., Competing Interests: Competing interests: SRAW: has, within the last 5 years, received a grant from GlaxoSmithKline. GB: Has, within the last 5 years, received honoraria for lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva; he is a member of advisory boards for AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva. ER: has, within the last 5 years, received research grants and/or speakers’ fees from MSD, Amgen, Boehringer Ingelheim, Sanofi/Regeneron and Teva. LL: has, within the last 5 years, received respiratory society awards sponsored by AstraZeneca and Chiesi and performed expert consultation for Boehringer Ingelheim GmbH and Novartis. DB, MG, MV and NT have nothing to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although obesity is associated with the development and progression of atrial fibrillation (AF), an obesity paradox may be present, illustrated by seemingly protective effects of obesity on AF-related outcomes. Body mass index (BMI) has an impact on outcomes in AF patients using oral anticoagulants. After searching Medline and Embase, meta-analysis of results of four randomized and five observational studies demonstrated significantly lower risks of stroke or systemic embolism (RR 0.80, 95%CI [0.73-0.87]; RR 0.63, 95%CI [0.57-0.70]; and RR 0.42, 95%CI [0.31-0.57], respectively) and all-cause mortality (RR 0.73, 95%CI [0.64-0.83]; RR 0.61, 95%CI [0.52-0.71]; and RR 0.56, 95%CI [0.47-0.66], respectively) in overweight, obese and morbidly obese anticoagulated AF patients (BMI 25 to <30, ≥30 and ≥40 kg/m 2 , respectively) compared to normal BMI anticoagulated AF patients (BMI 18.5 to <25 kg/m 2 ). In contrast, thromboembolic (RR 1.92, 95%CI [1.28-2.90]) and mortality (RR 3.57, 95%CI [2.50-5.11]) risks were significantly increased in underweight anticoagulated AF patients (BMI <18.5 kg/m 2 ). In overweight and obese anticoagulated AF patients, the risks of major bleeding (RR 0.86, 95%CI [0.76-0.99]; and RR 0.88, 95%CI [0.79-0.98], respectively) and intracranial bleeding (RR 0.75, 95%CI [0.58-0.97]; and RR 0.57, 95%CI [0.40-0.80], respectively) were also significantly lower compared to normal BMI patients, while similar risks were observed in underweight and morbidly obese patients. This meta-analysis demonstrated lower thromboembolic and mortality risks with increasing BMI. However, as this paradox was driven by results from randomized studies, while observational studies rendered more conflicting results, these seemingly protective effects should still be interpreted with caution., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: This study aimed to evaluate the prevalence of potential drug-drug interactions (DDIs) and the appropriateness of direct oral anticoagulant (DOAC) dosing according to both the Summary of Product Characteristics (SmPC) and the European Heart Rhythm Association (EHRA) Practical Guide in a 'real-world' sample of non-valvular atrial fibrillation (NVAF) patients., Methods and Results: Data of a cross-sectional observational study in a primary care sample of 654 long-term DOAC users were used for this sub-analysis. A total of 262 potential DDIs were identified in 220 patients (33.6%). Pharmacodynamic DDIs were present in 163 patients (24.9%) and pharmacokinetic DDIs in 82 patients (12.5%). One-third of patients (33.8%) received reduced DOAC dose. According to the dosing recommendations in the SmPC, 81.7% of DOACs were dosed appropriately. According to the EHRA recommendations, 76.6% of DOACs were dosed appropriately. Dosing recommendations were consistent for 90.7% of patients, with both the SmPC and EHRA Practical Guide considering DOACs dosed appropriately in 74.5% of patients, overdosed in 7.8%, underdosed in 7.6% and contraindicated in 0.8%. However, for the remaining 9.3% dosing recommendations differed between SmPC and EHRA., Conclusions: This 'real-world' analysis of DOAC dosing demonstrated that in about one-third of NVAF patients potential DDIs were present. In 18.3% and 23.4% of patients, DOACs were dosed inappropriately according to the SmPC and EHRA Practical Guide respectively. In almost 10% of the study population dosing advice was inconsistent between both references. More research is needed to ensure appropriate DOAC dosing in this 'grey zone' population., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Oral anticoagulants (OACs) are crucial for treating atrial fibrillation (AF) patients at high thromboembolic risk. However, in AF patients at intermediate thromboembolic risk with a single non-sex-related stroke risk factor (CHA 2 DS 2 -VASc score 1 in men, 2 in women), guidelines advise to consider starting anticoagulation, which may result in OAC non-initiation due to underestimation of the thromboembolic risk of a single stroke risk factor and overestimation of the OAC-related bleeding risk. A critical appraisal of the role of OACs and the benefit-risk profile of non-vitamin K antagonist oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) in this patient subgroup are needed., Methods and Results: This systematic review provides an overview of literature on the effectiveness and safety of OACs in AF patients with a single non-sex-related stroke risk factor after searching Medline and Embase. Differences between individual stroke risk factors regarding the ischaemic stroke risk in non-anticoagulated AF patients are identified in a meta-analysis, demonstrating the highest increased risk in patients aged 65-74 years old or with diabetes mellitus, followed by heart failure, hypertension and vascular disease. Furthermore, meta-analysis results favour NOACs over VKAs, given their equal effectiveness and superior safety in AF patients at intermediate thromboembolic risk (HR 0.93, 95% CI 0.65 to 1.34 for stroke or systemic embolism; HR 0.60, 95% CI 0.45 to 0.80 for major bleeding; HR 0.48, 95% CI 0.14 to 1.59 for intracranial bleeding; HR 0.58, 95% CI 0.47 to 0.71 for mortality)., Conclusion: Our systematic review with meta-analysis favours the use of anticoagulation in AF patients with a single non-sex-related stroke risk factor, especially when age ≥65 years or diabetes mellitus is present, with a preference for NOACs over VKAs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic obstructive pulmonary disease (COPD) has been associated with atrial fibrillation (AF). More insight into the epidemiology and underlying mechanisms is required to optimize management., Methods: The Rotterdam Study is a large, population-based cohort study with long-term follow-up. Time dependent Cox proportional hazard models were constructed to study the effect of COPD on incident AF, adjusted for age, sex and pack years of cigarette smoking, and additionally stratified according to exacerbation frequency, left atrial size and baseline systemic inflammatory levels., Results: 1369 of 10,943 subjects had COPD, of whom 804 developed AF. The AF incidence rate was 14 per 1000 person years in COPD and 8 per 1000 person years in subjects without COPD. The adjusted hazard ratio (HR) for COPD subjects to develop AF as compared to subjects without COPD was 1.28 (95%CI [1.04, 1.57]). COPD subjects with frequent exacerbations had a twofold increased AF risk (HR 1.99 [1.42, 2.79]) and COPD subjects with a left atrial size ≥40 mm also had an elevated AF risk (HR 1.77 [1.07, 2.94]). COPD subjects with baseline systemic inflammatory levels above the median had significantly increased AF risks (hsCRP≥1.83 mg/L: HR 1.51 [1.13, 2.03] and IL6 ≥ 1.91 ng/L: HR 2.49 [1.18, 5.28]), whereas COPD subjects below the median had in both analyses no significantly increased AF risk., Conclusions: COPD subjects had a 28% increased AF risk, which further increased with frequent exacerbations and an enlarged left atrium. The risk was driven by COPD subjects having elevated systemic inflammatory levels., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)